The long-term goal of our research is to find treatments for the prevention of the disorders associated with menopause which are safer and more efficacious than present hormone replacement therapy (HRT). The failure of present HRT to fulfill medical and women's needs has to be ascribed to an insufficient knowledge of the biology of menopause. The aim of our research is focused on the understanding the consequences of cessation of ovarian functions on the physiology of non-reproductive organs such as bone, brain, arteries and fat. In particular our studies and the studies proposed in the present project will focus on the effects of estrogen decreased production at menopause transition and after in non-reproductive organs. Given recent results demonstrating that in non-reproductive organs of fertile female mice estrogen receptors (ERs) are activated by factors other than estrogens, our Specific Aim #1 will focus on assessing the extent to which ERs are transcriptionally active during menopause transition and after. We will then try to identify the factor(s) involved in ER activation. This part of the project relates to questions which so far could be addressed only partially with the current technology. The generation of a novel model of reporter system, the ERE-Luc mouse, will enable us to precisely quantify ER activity in the organs of interest and facilitate the search of factors involved in ER unliganded activation. Specific Aim #2 will give us the opportunity to test an original hypothesis that would explain the widespread protective effects provided by the estrogen-ER system. This hypothesis is based on numerous very recent observations made in ours and several other groups showing that estrogens and cognate receptors may exert a strong anti-inflammatory action by inhibiting the immune response of cells of the monocyte lineage. We here propose that menopause consists in a decreased response to increased inflammation. We will test this hypothesis by the direct assessment of ER relevance on macrophage activity through the generation of a novel conditional ERalpha K.O. mouse. Furthermore, using brain as a paradigmatic non-reproductive organ, we will measure basal and induced activity of brain inflammatory cells. Finally, the specific involvement of ER anti-inflammatory activity in the development of menopause-associated diseases will be tested with the study of the activity in menopause of another class of intracellular receptors devoted to the control of inflammation, the PPARs.